Gonadotropin-releasing hormone (GnRH) and the subsequent release of luteinizing hormone (LH) is the final common pathway for the neuroendocrine control of reproduction. The factors regulating GnRH release are poorly understood. The recent discovery of the co-expression of the peptide orphanin FQ/nociceptin (OFQ/N) with almost all GnRH neurons in both sexes and in turn the ability of OFQ/N to reduce GnRH release in vitro suggests OFQ/N plays a part in the control of GnRH neuronal activity. The experiments herein will establish: a) if, as in hypothalamic blocks, OFQ/N can inhibit GnRH/LH release in vivo; b) if OFQ/N acts through its receptor, opioid receptor like-1 receptor (ORL-1), to directly effect GnRH neurons and/or gonadotropes; and c) if OFQ/N directly regulates GnRH/LH expression levels through ORL-1. Overall these studies will provide important information about the mechanisms regulating GnRH neuronal activity and the corresponding release of LH.